Critical Care

Outcomes for mechanically ventilated adults with sepsis receiving light sedation were the same whether they received dexmedetomidine or propofol, according to data from a 13-center randomized, controlled, double-blind study published online Feb. 2 in the New England Journal of Medicine.

Dexmedetomidine (an alpha2-receptor agonist) and propofol (a gamma-aminobutyric acid [GABA]–receptor agonist) have similar safety profiles.

The findings from the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure (MENDS2) trial were published on an accelerated schedule to coincide with the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Lead author Christopher G. Hughes, MD, chief of anesthesiology in critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., told this news organization that previous trials have shown that dexmedetomidine is likely superior to benzodiazepines, especially in improving delirium, coma, and time on a ventilator. Until this trial, dexmedetomidine’s performance in a head-to-head comparison with propofol – the current standard-of-care agent – was not clear.

Researchers discovered that, “despite theoretical advantages of dexmedetomidine, that did not translate into the clinical realm when patients were receiving up-to-date sedation care,” he said.

Guidelines currently recommend either drug when light sedation is needed for adults on ventilators. The drugs are different in the way they affect arousability, immunity, and inflammation, but a comparison of outcomes in adults with sepsis – in terms of days alive without brain dysfunction – had never before been performed in a randomized, controlled trial.

In this trial, 422 patients were randomly assigned to receive either dexmedetomidine (0.15-1.5 mcg/kg of body weight per hour) or propofol (5-50 mcg/kg per minute). Doses were adjusted by bedside nurses (who were unblinded) to achieve specified sedation goals.

The primary outcome was days alive without delirium or coma in the 14 days of intervention. The researchers found no difference between the two groups (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval, 0.74-1.26).

There was also little difference in three secondary outcomes: ventilator-free days (adjusted median, 23.7 vs. 24.0 days; OR, 0.98); death at 90 days (38% vs. 39%; hazard ratio, 1.06); or the Telephone Interview for Cognitive Status (TICS) Total score measuring global cognition at 6 months (adjusted median score, 40.9 vs. 41.4; OR, 0.94).

Dr. Hughes said the researchers “specifically went with a high-severity-of-illness cohort that would be most likely to see an effect.”

He said the drugs have different adverse-effect profiles, so a clinician can consider those in deciding between the two, but either should be fine at baseline.

The researchers note that at least 20 million patients each year develop sepsis with severe organ dysfunction, and more than 20% receive mechanical ventilation.
 

Confirmation of current guidelines

Sandra Kane-Gill, PharmD, president-elect of SCCM, stated in an interview that she is impressed with the study design and said the results give definitive confirmation of current guidelines.

“The rigorous study design is different from previous comparative-effectiveness trials on the drugs in this group of patients,” she said.

As to what clinicians think about when choosing one over the other, Dr. Kane-Gill said that with dexmedetomidine, there may be more concern about bradycardia, whereas propofol may be associated with concerns of high triglycerides.

“There may be more comfort with use of propofol,” and dexmedetomidine can be more costly than propofol, she added, so those could be factors in decision-making as well.

Dr. Hughes said this study offers a robust look at cognition after the ICU, which is getting increasing attention.

“We had a much more extensive cognitive battery we performed on patients than in previous studies,” Dr. Hughes said, “and it’s important that we did not find a difference in either the main cognition or the other cognitive scores between the two agents.”

Enrollment was completed before the pandemic, but he said the results are relevant to COVID-19 patients because those who are on ventilators in the ICU are in a sick, septic-shock cohort.

“COVID patients would be the type of patients we enrolled in this study,” he said, “with the high severity of illness and the infection on top of being on a ventilator. We know that sedation regimens have been challenging in COVID patients.”

Dr. Hughes and Dr. Kane-Gill have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Outcomes for mechanically ventilated adults with sepsis receiving light sedation were the same whether they received dexmedetomidine or propofol, according to data from a 13-center randomized, controlled, double-blind study published online Feb. 2 in the New England Journal of Medicine.

Dexmedetomidine (an alpha2-receptor agonist) and propofol (a gamma-aminobutyric acid [GABA]–receptor agonist) have similar safety profiles.

The findings from the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure (MENDS2) trial were published on an accelerated schedule to coincide with the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Lead author Christopher G. Hughes, MD, chief of anesthesiology in critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., told this news organization that previous trials have shown that dexmedetomidine is likely superior to benzodiazepines, especially in improving delirium, coma, and time on a ventilator. Until this trial, dexmedetomidine’s performance in a head-to-head comparison with propofol – the current standard-of-care agent – was not clear.

Researchers discovered that, “despite theoretical advantages of dexmedetomidine, that did not translate into the clinical realm when patients were receiving up-to-date sedation care,” he said.

Guidelines currently recommend either drug when light sedation is needed for adults on ventilators. The drugs are different in the way they affect arousability, immunity, and inflammation, but a comparison of outcomes in adults with sepsis – in terms of days alive without brain dysfunction – had never before been performed in a randomized, controlled trial.

In this trial, 422 patients were randomly assigned to receive either dexmedetomidine (0.15-1.5 mcg/kg of body weight per hour) or propofol (5-50 mcg/kg per minute). Doses were adjusted by bedside nurses (who were unblinded) to achieve specified sedation goals.

The primary outcome was days alive without delirium or coma in the 14 days of intervention. The researchers found no difference between the two groups (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval, 0.74-1.26).

There was also little difference in three secondary outcomes: ventilator-free days (adjusted median, 23.7 vs. 24.0 days; OR, 0.98); death at 90 days (38% vs. 39%; hazard ratio, 1.06); or the Telephone Interview for Cognitive Status (TICS) Total score measuring global cognition at 6 months (adjusted median score, 40.9 vs. 41.4; OR, 0.94).

Dr. Hughes said the researchers “specifically went with a high-severity-of-illness cohort that would be most likely to see an effect.”

He said the drugs have different adverse-effect profiles, so a clinician can consider those in deciding between the two, but either should be fine at baseline.

The researchers note that at least 20 million patients each year develop sepsis with severe organ dysfunction, and more than 20% receive mechanical ventilation.
 

Confirmation of current guidelines

Sandra Kane-Gill, PharmD, president-elect of SCCM, stated in an interview that she is impressed with the study design and said the results give definitive confirmation of current guidelines.

“The rigorous study design is different from previous comparative-effectiveness trials on the drugs in this group of patients,” she said.

As to what clinicians think about when choosing one over the other, Dr. Kane-Gill said that with dexmedetomidine, there may be more concern about bradycardia, whereas propofol may be associated with concerns of high triglycerides.

“There may be more comfort with use of propofol,” and dexmedetomidine can be more costly than propofol, she added, so those could be factors in decision-making as well.

Dr. Hughes said this study offers a robust look at cognition after the ICU, which is getting increasing attention.

“We had a much more extensive cognitive battery we performed on patients than in previous studies,” Dr. Hughes said, “and it’s important that we did not find a difference in either the main cognition or the other cognitive scores between the two agents.”

Enrollment was completed before the pandemic, but he said the results are relevant to COVID-19 patients because those who are on ventilators in the ICU are in a sick, septic-shock cohort.

“COVID patients would be the type of patients we enrolled in this study,” he said, “with the high severity of illness and the infection on top of being on a ventilator. We know that sedation regimens have been challenging in COVID patients.”

Dr. Hughes and Dr. Kane-Gill have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Outcomes for mechanically ventilated adults with sepsis receiving light sedation were the same whether they received dexmedetomidine or propofol, according to data from a 13-center randomized, controlled, double-blind study published online Feb. 2 in the New England Journal of Medicine.

Dexmedetomidine (an alpha2-receptor agonist) and propofol (a gamma-aminobutyric acid [GABA]–receptor agonist) have similar safety profiles.

The findings from the Maximizing the Efficacy of Sedation and Reducing Neurological Dysfunction and Mortality in Septic Patients with Acute Respiratory Failure (MENDS2) trial were published on an accelerated schedule to coincide with the Critical Care Congress sponsored by the Society of Critical Care Medicine.

Lead author Christopher G. Hughes, MD, chief of anesthesiology in critical care medicine at Vanderbilt University Medical Center, Nashville, Tenn., told this news organization that previous trials have shown that dexmedetomidine is likely superior to benzodiazepines, especially in improving delirium, coma, and time on a ventilator. Until this trial, dexmedetomidine’s performance in a head-to-head comparison with propofol – the current standard-of-care agent – was not clear.

Researchers discovered that, “despite theoretical advantages of dexmedetomidine, that did not translate into the clinical realm when patients were receiving up-to-date sedation care,” he said.

Guidelines currently recommend either drug when light sedation is needed for adults on ventilators. The drugs are different in the way they affect arousability, immunity, and inflammation, but a comparison of outcomes in adults with sepsis – in terms of days alive without brain dysfunction – had never before been performed in a randomized, controlled trial.

In this trial, 422 patients were randomly assigned to receive either dexmedetomidine (0.15-1.5 mcg/kg of body weight per hour) or propofol (5-50 mcg/kg per minute). Doses were adjusted by bedside nurses (who were unblinded) to achieve specified sedation goals.

The primary outcome was days alive without delirium or coma in the 14 days of intervention. The researchers found no difference between the two groups (adjusted median, 10.7 vs. 10.8 days; odds ratio, 0.96; 95% confidence interval, 0.74-1.26).

There was also little difference in three secondary outcomes: ventilator-free days (adjusted median, 23.7 vs. 24.0 days; OR, 0.98); death at 90 days (38% vs. 39%; hazard ratio, 1.06); or the Telephone Interview for Cognitive Status (TICS) Total score measuring global cognition at 6 months (adjusted median score, 40.9 vs. 41.4; OR, 0.94).

Dr. Hughes said the researchers “specifically went with a high-severity-of-illness cohort that would be most likely to see an effect.”

He said the drugs have different adverse-effect profiles, so a clinician can consider those in deciding between the two, but either should be fine at baseline.

The researchers note that at least 20 million patients each year develop sepsis with severe organ dysfunction, and more than 20% receive mechanical ventilation.
 

Confirmation of current guidelines

Sandra Kane-Gill, PharmD, president-elect of SCCM, stated in an interview that she is impressed with the study design and said the results give definitive confirmation of current guidelines.

“The rigorous study design is different from previous comparative-effectiveness trials on the drugs in this group of patients,” she said.

As to what clinicians think about when choosing one over the other, Dr. Kane-Gill said that with dexmedetomidine, there may be more concern about bradycardia, whereas propofol may be associated with concerns of high triglycerides.

“There may be more comfort with use of propofol,” and dexmedetomidine can be more costly than propofol, she added, so those could be factors in decision-making as well.

Dr. Hughes said this study offers a robust look at cognition after the ICU, which is getting increasing attention.

“We had a much more extensive cognitive battery we performed on patients than in previous studies,” Dr. Hughes said, “and it’s important that we did not find a difference in either the main cognition or the other cognitive scores between the two agents.”

Enrollment was completed before the pandemic, but he said the results are relevant to COVID-19 patients because those who are on ventilators in the ICU are in a sick, septic-shock cohort.

“COVID patients would be the type of patients we enrolled in this study,” he said, “with the high severity of illness and the infection on top of being on a ventilator. We know that sedation regimens have been challenging in COVID patients.”

Dr. Hughes and Dr. Kane-Gill have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who received telemedicine in an intensive care unit were less likely to die and more likely to have a shorter hospital stay than those who received standard ICU care without a 24-hour intensivist on-site, new data suggest.

Chiedozie I. Udeh, MD, staff intensivist with the Cleveland Clinic Foundation, presented results of a retrospective study of 153,987 consecutive ICU patients at the Critical Care Congress sponsored by the Society of Critical Care Medicine. .

Among the statistically significant findings were that 30-day mortality decreased by 18% (odds ratio, 0.82; 95% confidence interval, 0.77-0.87) and length of stay in the ICU decreased by 1.6 days in the telehealth model (95% CI, 1.5-1.7), compared with the traditional model. The total length of the average hospital stay was reduced by 2.1 days (95% CI, 1.9-2.4).

Patients in the study received ICU care at one of nine Cleveland Clinic hospitals between Jan. 1, 2010, and Dec. 31, 2019. Overall, 108,482 (70%) received ICU-telemedicine care during hours when an intensivist was not on-site.

Dr. Udeh said in an interview that only the largest academic centers typically have an intensivist on-site 24 hours a day. In the traditional model, critical care specialists may be on-site during the day but on call after hours.

In the tele-ICU model, in contrast, an intensivist – perhaps at a command center serving several hospitals – can observe and order treatments for patients remotely. The specialist has access to the patient’s medical record and test results, can monitor vital signs and visible changes, and can talk with both the patient and the nurse or other provider in the room.

Dr. Udeh said he suspects the 18% drop in mortality risk and the shorter hospital stay come from time saved. The physician doesn’t have to ask the nurse to look up health information and with constant monitoring can spot problems sooner or prevent them.

“You reduce a lot of the time from event to intervention or prevent an event by being more proactive,” Dr. Udeh said.

Ben Scott, MD, associate professor of anesthesiology and critical care at the University of Colorado at Denver, Aurora, said in an interview that his institution uses the tele-ICU model in several of the smaller hospitals there and is not surprised that Dr. Udeh’s team found such positive results. Dr. Scott was not involved in Dr. Udeh’s study.

“Most of us who have been working in this area and studying the results believe that these programs can make a big difference,” said Dr. Scott, vice chair for the SCCM tele-critical-care committee.

The smaller UC hospitals have ICU capability but not the census numbers to warrant 24-hour intensivist coverage. Of course, they do have 24-hour nursing coverage, and they typically use telemedicine when an intensivist is needed during the night, Dr. Scott said.
 

Hard to pinpoint telemedicine’s role

Dr. Scott said it’s hard to determine from studies how much telemedicine is influencing outcomes, compared with potentially confounding factors. A hospital with several ICUs might choose to send a patient to a certain ICU for a particular reason, which could confound comparisons.

The statistical techniques Dr. Udeh’s team used, however, helped account for confounding, Dr. Scott said. The extended years for the study and large patient sample also strengthen confidence in the results, he said.

The researchers found that several factors can increase an ICU patient’s risk of dying, including the reason for admission (such as cardiac arrest or sepsis), being admitted on a weekend, and the patient’s race. But they found that telemedicine might mitigate the effects of weekend admissions; the telemedicine patients admitted on a weekend in this study were no more likely to die than those admitted on a weekday.

The telemedicine model is especially important in areas without intensivists.

“If my only recourse is to send my patient out of town or out of state to another hospital, it’s a win-win,” Dr. Udeh said.

Regardless of the resources of individual hospitals, the national picture is clear, he said. “We just don’t have enough people trained in critical care to place an intensivist in every ICU 24/7.”

In late January, Santa Cruz Valley Regional Hospital in Green Valley, Ariz., temporarily shut down its ICU. The hospital CEO said the closure came because the hospital was unable to hire a pulmonologist.
 

Balancing cost issues

Cost issues with the tele-ICU have been a barrier for widespread adoption, Dr. Udeh said. He estimated that only about 15%-20% of hospitals incorporate the model.

Hospitals must pay for hardware and the telehealth service while still needing to have someone on staff available to come in if a physician’s presence is needed. And so far, those costs are not generally reimbursable by payers.

Hospitals must balance the costs with the potential for better outcomes and shorter stays, he said.

The model has benefits for the provider as well.

Dr. Udeh recounted being awakened by a call in the middle of the night and fighting off grogginess to quickly process information and make critical decisions.

But with the tele-ICU model, providers are awake for a specified shift and are periodically rounding on patients electronically with real-time access to health information.

Dr. Udeh said many of the tele-ICU platforms have decision support built in, with various degrees of complexity, so that the system might flag when a patient’s blood pressure is trending down, for example.

Although this research used prepandemic data, COVID-19 has highlighted the need for solutions to stretch ICU workforces.

Dr. Scott pointed out that in the pandemic, many hospitals that don’t have regular critical care services have had to take care of critically ill patients.

Having a telemedicine program can help bring that expertise to the bedside, he said.

Dr. Udeh, his coinvestigators, and Dr. Scott have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who received telemedicine in an intensive care unit were less likely to die and more likely to have a shorter hospital stay than those who received standard ICU care without a 24-hour intensivist on-site, new data suggest.

Chiedozie I. Udeh, MD, staff intensivist with the Cleveland Clinic Foundation, presented results of a retrospective study of 153,987 consecutive ICU patients at the Critical Care Congress sponsored by the Society of Critical Care Medicine. .

Among the statistically significant findings were that 30-day mortality decreased by 18% (odds ratio, 0.82; 95% confidence interval, 0.77-0.87) and length of stay in the ICU decreased by 1.6 days in the telehealth model (95% CI, 1.5-1.7), compared with the traditional model. The total length of the average hospital stay was reduced by 2.1 days (95% CI, 1.9-2.4).

Patients in the study received ICU care at one of nine Cleveland Clinic hospitals between Jan. 1, 2010, and Dec. 31, 2019. Overall, 108,482 (70%) received ICU-telemedicine care during hours when an intensivist was not on-site.

Dr. Udeh said in an interview that only the largest academic centers typically have an intensivist on-site 24 hours a day. In the traditional model, critical care specialists may be on-site during the day but on call after hours.

In the tele-ICU model, in contrast, an intensivist – perhaps at a command center serving several hospitals – can observe and order treatments for patients remotely. The specialist has access to the patient’s medical record and test results, can monitor vital signs and visible changes, and can talk with both the patient and the nurse or other provider in the room.

Dr. Udeh said he suspects the 18% drop in mortality risk and the shorter hospital stay come from time saved. The physician doesn’t have to ask the nurse to look up health information and with constant monitoring can spot problems sooner or prevent them.

“You reduce a lot of the time from event to intervention or prevent an event by being more proactive,” Dr. Udeh said.

Ben Scott, MD, associate professor of anesthesiology and critical care at the University of Colorado at Denver, Aurora, said in an interview that his institution uses the tele-ICU model in several of the smaller hospitals there and is not surprised that Dr. Udeh’s team found such positive results. Dr. Scott was not involved in Dr. Udeh’s study.

“Most of us who have been working in this area and studying the results believe that these programs can make a big difference,” said Dr. Scott, vice chair for the SCCM tele-critical-care committee.

The smaller UC hospitals have ICU capability but not the census numbers to warrant 24-hour intensivist coverage. Of course, they do have 24-hour nursing coverage, and they typically use telemedicine when an intensivist is needed during the night, Dr. Scott said.
 

Hard to pinpoint telemedicine’s role

Dr. Scott said it’s hard to determine from studies how much telemedicine is influencing outcomes, compared with potentially confounding factors. A hospital with several ICUs might choose to send a patient to a certain ICU for a particular reason, which could confound comparisons.

The statistical techniques Dr. Udeh’s team used, however, helped account for confounding, Dr. Scott said. The extended years for the study and large patient sample also strengthen confidence in the results, he said.

The researchers found that several factors can increase an ICU patient’s risk of dying, including the reason for admission (such as cardiac arrest or sepsis), being admitted on a weekend, and the patient’s race. But they found that telemedicine might mitigate the effects of weekend admissions; the telemedicine patients admitted on a weekend in this study were no more likely to die than those admitted on a weekday.

The telemedicine model is especially important in areas without intensivists.

“If my only recourse is to send my patient out of town or out of state to another hospital, it’s a win-win,” Dr. Udeh said.

Regardless of the resources of individual hospitals, the national picture is clear, he said. “We just don’t have enough people trained in critical care to place an intensivist in every ICU 24/7.”

In late January, Santa Cruz Valley Regional Hospital in Green Valley, Ariz., temporarily shut down its ICU. The hospital CEO said the closure came because the hospital was unable to hire a pulmonologist.
 

Balancing cost issues

Cost issues with the tele-ICU have been a barrier for widespread adoption, Dr. Udeh said. He estimated that only about 15%-20% of hospitals incorporate the model.

Hospitals must pay for hardware and the telehealth service while still needing to have someone on staff available to come in if a physician’s presence is needed. And so far, those costs are not generally reimbursable by payers.

Hospitals must balance the costs with the potential for better outcomes and shorter stays, he said.

The model has benefits for the provider as well.

Dr. Udeh recounted being awakened by a call in the middle of the night and fighting off grogginess to quickly process information and make critical decisions.

But with the tele-ICU model, providers are awake for a specified shift and are periodically rounding on patients electronically with real-time access to health information.

Dr. Udeh said many of the tele-ICU platforms have decision support built in, with various degrees of complexity, so that the system might flag when a patient’s blood pressure is trending down, for example.

Although this research used prepandemic data, COVID-19 has highlighted the need for solutions to stretch ICU workforces.

Dr. Scott pointed out that in the pandemic, many hospitals that don’t have regular critical care services have had to take care of critically ill patients.

Having a telemedicine program can help bring that expertise to the bedside, he said.

Dr. Udeh, his coinvestigators, and Dr. Scott have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients who received telemedicine in an intensive care unit were less likely to die and more likely to have a shorter hospital stay than those who received standard ICU care without a 24-hour intensivist on-site, new data suggest.

Chiedozie I. Udeh, MD, staff intensivist with the Cleveland Clinic Foundation, presented results of a retrospective study of 153,987 consecutive ICU patients at the Critical Care Congress sponsored by the Society of Critical Care Medicine. .

Among the statistically significant findings were that 30-day mortality decreased by 18% (odds ratio, 0.82; 95% confidence interval, 0.77-0.87) and length of stay in the ICU decreased by 1.6 days in the telehealth model (95% CI, 1.5-1.7), compared with the traditional model. The total length of the average hospital stay was reduced by 2.1 days (95% CI, 1.9-2.4).

Patients in the study received ICU care at one of nine Cleveland Clinic hospitals between Jan. 1, 2010, and Dec. 31, 2019. Overall, 108,482 (70%) received ICU-telemedicine care during hours when an intensivist was not on-site.

Dr. Udeh said in an interview that only the largest academic centers typically have an intensivist on-site 24 hours a day. In the traditional model, critical care specialists may be on-site during the day but on call after hours.

In the tele-ICU model, in contrast, an intensivist – perhaps at a command center serving several hospitals – can observe and order treatments for patients remotely. The specialist has access to the patient’s medical record and test results, can monitor vital signs and visible changes, and can talk with both the patient and the nurse or other provider in the room.

Dr. Udeh said he suspects the 18% drop in mortality risk and the shorter hospital stay come from time saved. The physician doesn’t have to ask the nurse to look up health information and with constant monitoring can spot problems sooner or prevent them.

“You reduce a lot of the time from event to intervention or prevent an event by being more proactive,” Dr. Udeh said.

Ben Scott, MD, associate professor of anesthesiology and critical care at the University of Colorado at Denver, Aurora, said in an interview that his institution uses the tele-ICU model in several of the smaller hospitals there and is not surprised that Dr. Udeh’s team found such positive results. Dr. Scott was not involved in Dr. Udeh’s study.

“Most of us who have been working in this area and studying the results believe that these programs can make a big difference,” said Dr. Scott, vice chair for the SCCM tele-critical-care committee.

The smaller UC hospitals have ICU capability but not the census numbers to warrant 24-hour intensivist coverage. Of course, they do have 24-hour nursing coverage, and they typically use telemedicine when an intensivist is needed during the night, Dr. Scott said.
 

Hard to pinpoint telemedicine’s role

Dr. Scott said it’s hard to determine from studies how much telemedicine is influencing outcomes, compared with potentially confounding factors. A hospital with several ICUs might choose to send a patient to a certain ICU for a particular reason, which could confound comparisons.

The statistical techniques Dr. Udeh’s team used, however, helped account for confounding, Dr. Scott said. The extended years for the study and large patient sample also strengthen confidence in the results, he said.

The researchers found that several factors can increase an ICU patient’s risk of dying, including the reason for admission (such as cardiac arrest or sepsis), being admitted on a weekend, and the patient’s race. But they found that telemedicine might mitigate the effects of weekend admissions; the telemedicine patients admitted on a weekend in this study were no more likely to die than those admitted on a weekday.

The telemedicine model is especially important in areas without intensivists.

“If my only recourse is to send my patient out of town or out of state to another hospital, it’s a win-win,” Dr. Udeh said.

Regardless of the resources of individual hospitals, the national picture is clear, he said. “We just don’t have enough people trained in critical care to place an intensivist in every ICU 24/7.”

In late January, Santa Cruz Valley Regional Hospital in Green Valley, Ariz., temporarily shut down its ICU. The hospital CEO said the closure came because the hospital was unable to hire a pulmonologist.
 

Balancing cost issues

Cost issues with the tele-ICU have been a barrier for widespread adoption, Dr. Udeh said. He estimated that only about 15%-20% of hospitals incorporate the model.

Hospitals must pay for hardware and the telehealth service while still needing to have someone on staff available to come in if a physician’s presence is needed. And so far, those costs are not generally reimbursable by payers.

Hospitals must balance the costs with the potential for better outcomes and shorter stays, he said.

The model has benefits for the provider as well.

Dr. Udeh recounted being awakened by a call in the middle of the night and fighting off grogginess to quickly process information and make critical decisions.

But with the tele-ICU model, providers are awake for a specified shift and are periodically rounding on patients electronically with real-time access to health information.

Dr. Udeh said many of the tele-ICU platforms have decision support built in, with various degrees of complexity, so that the system might flag when a patient’s blood pressure is trending down, for example.

Although this research used prepandemic data, COVID-19 has highlighted the need for solutions to stretch ICU workforces.

Dr. Scott pointed out that in the pandemic, many hospitals that don’t have regular critical care services have had to take care of critically ill patients.

Having a telemedicine program can help bring that expertise to the bedside, he said.

Dr. Udeh, his coinvestigators, and Dr. Scott have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

Ceftolozane-tazobactam (C/T) was found effective for treating pneumonia, intra-abdominal, and urinary tract infections caused by Pseudomonas aeruginosa, according to the results of a retrospective, observational study conducted in critically ill patients.

The multicenter, observational study assessed 95 patients who received C/T for P. aeruginosa serious infections, according to a report published online in the International Journal of Antimicrobial Agents.

C/T is a novel beta-lactam/ beta-lactamase inhibitor combination active against gram-negative bacteria including P. aeruginosa, “This paper presents the largest real-life experience published on C/T therapy for treating serious P. aeruginosa infections according to researchers Barbara Balandin, MD, of the Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and colleagues.

The main infections treated were nosocomial pneumonia (56.2%), intra-abdominal infection (10.5%), tracheobronchitis (8.4%), and urinary tract infection (6.3%). Most infections were complicated with sepsis (49.5%) or septic shock (45.3%), and bacteremia (10.5%).

A total of 46 episodes were treated with high-dose C/T (3 g every 8 hours), and 38 episodes were treated with standard dosage (1.5 g every 8 hours). Almost half (44.2%) of the patients were treated with C/T monotherapy, and the remaining group received combination therapy with other antibiotics, according to the researchers.

The primary outcome of the study was to assess the efficacy and toxicity of C/T therapy. The secondary outcome was to evaluate the risk factors for all-cause 30-day mortality from the first day of therapy.

Favorable results

Most of the infections (93.7%) were severe and included the presence of sepsis (49.5%) or septic shock (45.3%). Bacteremia was observed in 15 (15.7%) patients. Bacteremia was secondary to nosocomial pneumonia in eight cases, catheter infection in five, urinary tract infection in one, and soft tissue infection in one. According to their susceptibility profiles, 46 (48.4%) of the strains were classified as extensively drug-resistant (XDR) P. aeruginosa and 35 (36.5%) were multidrug-resistant (MDR) P. aeruginosa.

Sixty-eight (71.6%) patients presented a favorable clinical response, which was defined as a resolution of presenting symptoms and signs of the infection by the end of therapy. An unfavorable clinical response was considered as persistence or worsening of the presenting symptoms and signs or death occurring during treatment with no other cause identified. Death associated with infection was defined as persistence of signs and symptoms of P. aeruginosa infection during C/T therapy with no other cause identified.

Microbiological eradication was documented in 42.1% (40/95) of the episodes. However, the global ICU mortality was still high, at 36.5%, with mortality mainly related to the severity of the infection.

Mortality was found to be significantly correlated with the Charlson Comorbidity Index (5.7 vs. 4.3; P = .04) and the need for life-supporting therapies such as vasopressors (66.6% vs. 46.9%; P = .03) and renal replacement therapy (46.6% vs. 18.1%; P = .002). In addition, mortality was significantly associated with a higher sequential organ failure assessment (SOFA) score during C/T therapy (SOFA1, SOFA 3, and SOFA 7; P < .001).

No significant differences in outcomes were correlated with demographic features, type and severity of infection, and dose of C/T. Also, there were no differences seen in outcomes between patients treated with C/T monotherapy and combined therapy (30.9% vs. 30.1%; P = .55).

“The lack of a positive effect from combined therapy suggests that C/T monotherapy may be sufficient for treating P. aeruginosa isolates that are susceptible to that agent,” the researchers suggested. “This study shows that C/T appears to be a suitable, effective, and safe drug for treating severe infections due to P. aeruginosa, highlighting nosocomial pneumonia caused by MDR/XDR P. aeruginosa in ICU patients with multiple comorbidities, such as immunosuppression, and needing life-sustaining therapies,” they concluded.

The authors reported that they had no outside funding source and had no conflicts of interest.

[email protected]

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Study Overview

Objective. To examine the trend of noninvasive and invasive mechanical ventilation at the end of life from 2000 to 2017.

Design. Observational population-based cohort study.

Setting and participants. The study was a population-based cohort study to examine the use of noninvasive and invasive mechanical ventilation among decedents. The study included a random 20% sample of Medicare beneficiaries older than 65 years who were hospitalized in the last 30 days of life and died between January 1, 2000, and December 31, 2017, except for the period October 1, 2015, to December 31, 2015, when the transition from International Classification of Diseases, Ninth Revision (ICD-9) to ICD-10 occurred. Beneficiaries with the primary admitting diagnosis of cardiac arrest or with preexisting tracheostomy were excluded because of expected requirements for ventilatory support. The sample included a total of 2,470,735 Medicare beneficiaries; mean age was 82.2 years, and 54.8% were female. Primary admitting diagnosis codes were used to identify 3 subcohorts: congestive heart failure, chronic obstructive pulmonary disease, and cancer; a fourth subcohort of dementia was identified using the primary admitting diagnosis code or the first 9 secondary diagnosis codes.

Main outcome measures. The study used procedure codes to identify the use of noninvasive ventilation, invasive mechanical ventilation, or none among decedents who were hospitalized in the last 30 days of life. Descriptive statistics to characterize variables by year of hospitalization and ventilatory support were calculated, and the rates of noninvasive and invasive mechanical ventilation use were tabulated. Other outcomes of interest include site of death (in-hospital death), hospice enrollment at death, and hospice enrollment in the last 3 days of life as measures of end-of- life care use. Multivariable logistic regressions were used to examine noninvasive and invasive mechanical ventilation use among decedents, and time trends were examined, with the pattern of use in year 2000 as reference. Subgroup analysis with the subcohort of patients with different diagnoses were conducted to examine trends.

Main results. From 2000 to 2017, 16.3% of decedents had invasive mechanical ventilation, 3.7% had noninvasive ventilation, and 1.0% had both noninvasive and invasive ventilation during their hospital stay. Compared to the reference year 2000, there was a 9-fold increase in noninvasive ventilation use, from 0.8% to 7.1% in 2017, and invasive mechanical ventilation use also increased slightly, from 15.0% to 18.5%. Compared to year 2000, decedents were 2.63 times and 1.04 times (adjusted odds ratio [OR]) more likely to receive noninvasive ventilation and invasive mechanical ventilation, respectively, in 2005, 7.87 times and 1.39 times more likely in 2011, and 11.84 times and 1.63 times more likely in 2017.

Subgroup analysis showed that for congestive heart failure and chronic obstructive pulmonary disease, the increase in noninvasive ventilation use mirrored the trend observed for the overall population, but the use of invasive mechanical ventilation did not increase from 2000 to 2017, with a rate of use of 11.1% versus 7.8% (adjusted OR, 1.07; 95% confidence interval [CI], 0.95-1.19) for congestive heart failure and 17.4% vs 13.2% (OR 1.03, 95% CI, 0.88-1.21) for chronic obstructive pulmonary disease. For the cancer and dementia subgroups, the increase in noninvasive ventilation use from 2000 to 2017 was accompanied by an increase in the use of invasive mechanical ventilation, with a rate of 6.2% versus 7.4% (OR, 1.40; 95% CI, 1.26-1.55) for decedents with cancer and a rate of 5.7% versus 6.2% (OR, 1.28; 95% CI, 1.17-1.41) for decedents with dementia. For other measures of end-of-life care, noninvasive ventilation use when compared to invasive mechanical ventilation use was associated with lower rates of in-hospital (acute care) deaths (50.3% vs 76.7%), hospice enrollment in the last 3 days of life (late hospice enrollment; 57.7% vs 63.0%), and higher rates of hospice enrollment at death (41.3% vs 20.0%).

Conclusion. There was an increase in the use of noninvasive ventilation from 2000 through 2017 among Medicare beneficiaries who died. The findings also suggest that the use of invasive mechanical ventilation did not increase among decedents with congestive heart failure and chronic obstructive pulmonary disease but increased among decedents with cancer and dementia.

Noninvasive ventilation offers an alternative to invasive mechanical ventilation for providing ventilatory support for respiratory failure, and may offer benefits as it could avert adverse effects associated with invasive mechanical ventilation, particularly in the management of respiratory failure due to congestive heart failure and chronic obstructive pulmonary disease.¹ There is evidence for potential benefits of use of noninvasive ventilation in other clinical scenarios, such as pneumonia in older adults with comorbidities, though its clinical utility is not as well established for other diseases.²

As noninvasive ventilation is introduced into clinical practice, it is not surprising that over the period of the study (2000 to 2017) that its use increased substantially. Advance directives that involve discussion of life-sustaining treatments, including in scenarios with respiratory failure, may also result in physician orders that specify whether an individual desires invasive mechanical ventilation versus other medical treatments, including noninvasive ventilation.^3,4 By examining the temporal trends of use of noninvasive and invasive ventilation, this study reveals that invasive mechanical ventilation use among decedents with dementia and cancer has increased, despite increases in the use of noninvasive ventilation. It is important to understand further what would explain these temporal trends and whether the use of noninvasive and also invasive mechanical ventilation at the end of life represents appropriate care with clear goals or whether it may represent overuse. It is also less clear in the end-of-life care scenario what the goals of treatment with noninvasive ventilation would be, especially if it does not avert the use of invasive mechanical ventilation.

The study includes decedents only, thus limiting the ability to draw conclusions about clinically appropriate care.⁵ Further studies should examine a cohort of patients who have serious and life-threatening illness to examine the trends and potential effects of noninvasive ventilation on outcomes and utilization, as individuals who have improved and survived would not be included in this present decedent cohort.

Applications for Clinical Practice

This study highlights changes in the use of noninvasive and invasive ventilation over time and the different trends seen among subgroups with different diagnoses. For older adults with serious comorbid illness such as dementia, it is especially important to have discussions on advance directives so that care at the end of life is concordant with the patient’s wishes and that unnecessary, burdensome care can be averted. Further studies to understand and define the appropriate use of noninvasive and invasive mechanical ventilation for older adults with significant comorbidities who have serious, life-threatening illness are needed to ensure appropriate clinical treatment at the end of life.

–William W. Hung, MD, MPH

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

Among people hospitalized with COVID-19, a combination of baricitinib and remdesivir reduces the median time to recovery, compared with remdesivir plus placebo, according to trial results published Dec. 11 in the New England Journal of Medicine.

Median time to recovery was 7 days for patients who received baricitinib versus 8 days for patients who received placebo.

The difference was greater in patients who required high-flow oxygen or noninvasive ventilation during their hospitalization. In this group, baricitinib shortened median time to recovery from 18 days to 10 days.

“Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status, notably among patients receiving high-flow oxygen or noninvasive mechanical ventilation,” reported Andre C. Kalil, MD, MPH, from the University of Nebraska Medical Center, Omaha, and colleagues. In addition, the combination was associated with fewer adverse events.

The study details data from the ACTT-2 trial that the Food and Drug Administration used to issue an emergency-use authorization for baricitinib in combination with remdesivir on Nov. 19.

Under the emergency-use authorization, baricitinib (Olumiant, Eli Lilly), a Janus kinase inhibitor approved for the treatment of rheumatoid arthritis, may be used in combination with remdesivir (Veklury, Gilead), an antiviral, for treating hospitalized adults and children aged at least 2 years with suspected or confirmed COVID-19.

The combination is intended for patients who need supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation.
 

Combo treatment favored

It is unclear how baricitinib compares with dexamethasone, which improved survival and led to a 1-day shorter hospital stay in another trial. There are differences between the drugs and trial designs, and only a “head-to-head comparison ... will allow the efficacy and safety differences between these two approaches to be fully understood,” Dr. Kalil and coauthors wrote.

“Dexamethasone has a long half-life, acts on glucocorticoid receptors, and reduces inflammation through a broad-pathway approach that has been associated with immunosuppression, hospital-acquired infections, gastrointestinal bleeding, hyperglycemia, and neuromuscular weakness, even with short courses,” they wrote. “Baricitinib has a short half-life, acts on targeted critical pathways to reduce inflammation while minimizing biologic redundancy with less immunosuppression, and may have antiviral activity.”

The ACTT-2 trial started in May and enrolled 1,033 patients in eight countries. Participants were randomly assigned to receive oral baricitinib tablets plus intravenous remdesivir or oral placebo tablets plus remdesivir. 

Participants who received both drugs had significantly improved clinical status at day 15. Patients who received both treatments also had fewer serious adverse events.

“Although ACTT-2 was not powered to detect a difference in mortality between the two groups, both the survival rate and the time-to-death analyses favored combination treatment,” the researchers wrote.

The trial was sponsored by the National Institute of Allergy and Infectious Diseases. Some of the authors disclosed funding from government grants and financial ties to Eli Lilly, Gilead, and other companies.

A version of this article originally appeared on Medscape.com.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

More patients are surviving critical illnesses requiring ICU care but many emerge with physical debility that may or may not eventually resolve.

Over the past decade, functional status deterioration after critical illness has become more common and of greater magnitude, despite concurrent efforts to reduce post–intensive care syndrome, based on a retrospective analysis of more than 100,000 patients.

Almost one-third of patients who survived nonsurgical ICU admission had evidence of functional status decline, reported lead author Nicholas E. Ingraham, MD, of the University of Minnesota, Minneapolis, and colleagues.

“Increasing capacity and decreasing mortality have created an evolving and diverse population of ICU survivors,” the investigators wrote in Critical Care Medicine. “Today’s survivors of critical illness are increasingly burdened by extensive physical and psychological comorbidities, often resulting in reduced quality of life.”

To determine trends in post–intensive care syndrome from 2008 to 2016, Dr. Ingraham and colleagues analyzed data from the Cerner Acute Physiology and Chronic Health Evaluation outcomes database, a national prospective cohort. Out of 202,786 adult patients admitted to the ICU, 129,917 were eligible for the study. Patients were excluded because of surgical admission, death, lack of functional status documentation, or inadequate hospital size or duration of participation. The final dataset had a median age of 63 years, with a slight predominance of male patients (54.0%). Most patients (80.9%) were White.

The primary outcome was defined as presence or absence of functional status deterioration, based on functional status at admission versus time of discharge. The secondary outcome was magnitude of deterioration over time.

The analysis, which controlled for age and severity of illness, revealed concerning trends for both outcomes.

Across the entire cohort 38,116 patients (29.3%) had functional status deterioration, with a 15% increase in prevalence over the course of the decade that spanned all disease categories (prevalence rate ratio, 1.15; 95% confidence interval, 1.13-1.17; P < .001). The magnitude of functional status decline also increased by 4% (odds ratio, 1.04; P < .001), with all but nonsurgical trauma patients showing greater deterioration over time.

“However, despite the decreasing magnitude of functional status deterioration in nonsurgical trauma, many admission diagnoses in this category remain in the top quartile of higher risk for functional status deterioration,” the investigators noted.

Functional status decline was most common among patients with head and polytrauma (OR, 3.39), followed closely by chest and spine trauma (OR, 3.38), and spine trauma (OR, 3.19). The top quartile of categories for prevalence of deterioration included nonsurgical trauma, neurologic, pulmonary, and gastrointestinal diseases.

Functional status decline was least common among patients diagnosed with diabetic ketoacidosis (OR, 0.27) or asthma (OR, 0.35).

“We believe our study provides important information that can be used in beginning to identify patients at high risk of functional status decline,” the investigators concluded. “Improving the identification of these patients and targeting appropriate interventions to mitigate this decline will be important directions for future studies in this area.”

According to David L. Bowton, MD, FCCP, professor emeritus, section on critical care, Wake Forest Baptist Health, Winston-Salem, N.C., the findings show just how common functional decline is after critical illness, and may actually underestimate prevalence.

“Because the authors employed a course evaluation tool employing only three categories of ability/disability and abstracted the level of disability from the medical record, they likely underestimated the frequency of clinically important, though not detected, disability at the time of hospital discharge,” Dr. Bowton said. “The study did not address cognitive impairment which can be detected in half of patients at 3 months following critical illness, and which significantly affects patients’ quality of life (Am J Respir Crit Care Med. 2020;202[2]:193-201).”

Dr. Bowton suggested that evidence-based methods of preventing post–intensive care syndrome are limited.

“Current efforts to improve post-ICU functional and cognitive outcomes suffer from the lack of proven effective interventions (Crit Care Med. 2019;47[11]:1607-18),” he said. “Observational data indicates that compliance with the ABCDEF bundle decreases the duration and incidence of delirium, ICU length of stay, duration of mechanical ventilation, and mortality (Crit Care Med. 2019;47[1]:3-14). However, the implications of these improvements on postdischarge functional outcomes are unknown as area the relative importance of individual elements of the bundle. Early mobility and patient and family diaries appear to improve functional status at discharge and postdischarge anxiety and depression, though the evidence supporting this is thin.”

Appropriate intervention may be especially challenging during the COVID-19 pandemic, he added.

“The impact of COVID on ICU staffing adequacy and stress is significant and the impact on quality bundle compliance and the availability of support services is currently not clear, but likely to be detrimental, especially to support services such as physical therapy that are already commonly understaffed,” Dr. Bowton said.

The study was supported by grants from the University of Minnesota’s Critical Care Research and Programmatic Development Program; the National Heart, Lung, and Blood Institute; and the University of Minnesota Clinical and Translational Science via the National Center for Advancing Translational Sciences. The investigators reported financial relationships with no other relevant organizations. Dr. Bowton reported no conflicts of interest.

SOURCE: Ingraham NE et al. Crit Care Med. 2020 Nov. doi: 10.1097/CCM.0000000000004524.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

Coronavirus disease 2019 (COVID-19), the disease caused by the highly contagious virus SARS-CoV-2, has affected over 45 million people worldwide and caused over 1.2 million deaths. Preventative strategies, including social distancing and facial coverings, have proven to be effective to decrease the risk of transmission. Unfortunately, despite these measures, a large number of individuals continue to get infected throughout the world. While most patients typically stay asymptomatic or develop mild forms of the disease, a fraction of them will progress to more severe forms that would necessitate hospital care. Since this is a novel virus, we do not have an effective antimicrobial agent and the care we provide is mostly supportive, aiming to prevent and treat the systemic complications produced by the virus and the inflammatory response that ensues.

The phases of COVID 19

COVID-19 can be clinically divided into three phases (Mason RJ, et al. Eur Respir J. 2020 Apr;55[4]).

The asymptomatic phase: Also known as incubation period. During this stage, the SARS-CoV-2 virus binds to the epithelial cells of the upper respiratory tract and starts replicating.

The viral phase: Associated with the classic constitutional symptoms such as fever, chills, headache, cough, fatigue, and diarrhea. This phase typically begins 4-6 days after exposure to SARS-CoV-2 and is characterized by high levels of viral replication and migration to the conducting airways, triggering the innate immune response.

The pulmonary phase: Characterized by hypoxia and ground glass infiltrates on computed tomography of the chest. By now, the virus has reached the respiratory bronchioles and the alveoli. During this phase (about 8-10 days after exposure) the virus begins to die, and the host immune response ensues. By now the number of viral units is very small, but the host immune reaction against the virus has begun to mount.

The tools in our toolbox: Timing is paramount

Remdesivir

The preliminary results from a recent trial that compared remdesivir with placebo, given 6-12 days from the onset of symptoms, revealed a shorter time to recovery with Remdesivir (Beigel JH, et al. N Engl J Med. 2020 Oct;8. NEJMoa2007764). The patients who received remdesivir within 10 days of the onset of symptoms had a shorter recovery time compared with those who received it after 10 days from the onset of symptoms. Moreover, remdesivir did not alter the disease course in patients who received the drug after the onset of hypoxia. These results are consistent with those of Wang and colleagues who reported no effect in time to clinical improvement in most patients who received the drug 10 days after the onset of symptoms (Wang Y, et al. Lancet. 2020 May;395[10236]:1569-78). In most antiviral trials, the agent was potentially given when the immune response had already begun, stage in which the number of viral units is not as large as in the earlier phases, possibly explaining the lack effect in time of clinical improvement or mortality.


Convalescent plasma

 Piechotta and colleagues recently showed that convalescent plasma, when given to patients more than 14 days from the onset of symptoms, provided no benefit in time to clinical improvement or 28-day mortality. At 14 days or later, the pulmonary phase (characterized by systemic inflammation) had started in nearly all patients. As it seems apparent, any intervention not targeted to modulate the inflammatory response is unlikely to make a difference in this stage. (Piechotta V, et al. Cochrane Database Syst Rev. 2020 Jul;7[7]:CD013600).

The negative results of these studies (antivirals and convalescent plasma) highlight the importance of timing. In most of these trials, the intervention was started at the end of the viral phase or in the pulmonary phase, when the virus was nearly or completely dead, but the host immune response has begun to mount.


Corticosteroids

Corticosteroids (methylprednisolone and dexamethasone) have shown positive effects when given at the proper time (beginning of the pulmonary phase). A recent study revealed a lower 28-day mortality when compared with placebo in hospitalized patients with COVID-19. However, a prespecified subgroup analysis showed no benefit and a signal of possible harm among those who received dexamethasone in the absence of hypoxia (viral phase) (Lim WS, et al. N Engl J Med. 2020 Jul;[NEJMoa2021436]). A meta-analysis of seven randomized trials that used different doses and types of corticosteroids (dexamethasone, methylprednisolone, and hydrocortisone) reported a lower 28-day mortality in the corticosteroids group. The benefit was more pronounced when the corticosteroids was used in critically ill patients who were not receiving invasive mechanical ventilation.


Self-proning

Self-proning is also thought to be beneficial during the pulmonary phase. Prone positioning for at least 3 hours improved oxygenation but the result was not sustained (Coppo A, et al. Lancet Respir Med. 2020 Aug;8[8]:765-74). A retrospective analysis of 199 patients with COVID-19 in the pulmonary phase who were being supported by high-flow nasal cannula showed that awake proning for more than 16 hours had no effect in the risk of intubation or mortality (Ferrando C, et al. reduce the use of critical care resources, and improve survival. We aimed to examine whether the combination of high-flow nasal oxygen therapy (HFNOCrit Care. 2020 [Oct];24[1]:597). There is concern that this intervention might produce a delay in intubation in patients who have worsening oxygenation; this is especially important as delayed intubation can be associated with worse outcomes. Despite the conflicting data, awake self-proning is a reasonable intervention that should be considered provided that it does not interfere with treatments that have been proven beneficial. As prospective evidence becomes available, recommendations may possibly change. 
 

What about thromboembolic events?

Data on arterial and venous thromboembolic events (VTE) in the disease course of COVID-19 are largely variable. The prevalence of VTE in COVID-19 seems to be higher than other in causes of sepsis especially in critically ill patients. (Bilaloglu S, et al. JAMA. 2020 Aug;324(8):799-801). Despite the use of pharmacological prophylaxis, VTE was seen in 13.6% of critically ill patients and 3.6% of medical ward patients and associated with a higher mortality. Therefore, more trials are needed to understand the most effective way to prevent VTE. At the current time, clinicians need to be vigilant to detect VTE as early as possible. Some options to consider include performing a daily evaluation of the possible risks (emphasizing prevention), routine bedside point of care ultrasound, early diagnostic imaging studies for clinically suspected VTE, early mobilization and delirium prevention. Prophylactic doses of LMWH or UH for all hospitalized patients with no or low risk of bleeding or non-hospitalized patient with high risk for VTE can be entertained (Bikdeli B, et al. J Am Coll Cardiol 2020 Apr;75[23]:2950-73). Therapeutic dose anticoagulation should be only used in confirmed VTE or in highly suspected VTE with difficulties to obtain standard confirmatory imaging. A therapeutic approach based solely on D-dimer should be avoided, because the evidence is insufficient and the risk of bleeding in critically ill patients is not insignificant.

Dr. Megri is a Pulmonary and Critical Care Fellow at the University of Kentucky. Dr. Coz is Associate Professor of Medicine, University of Kentucky.

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

A new consensus statement offers detailed guidelines for inpatient use of continuous glucose monitors (CGM) and automated insulin delivery (AID) systems.

Aimed at clinicians, researchers, and hospital administrators, the open-access document was recently published by a multidisciplinary international panel of 24 experts in the Journal of Diabetes Science and Technology.

The statement includes 77 separate recommendations under five headings: 1) continued use of CGM by patients already using them at home, 2) initiation of CGM in hospital, 3) continuation of AID systems in hospital by patients already using them at home, 4) logistics and hands-on care of hospitalized patients using CGM and AID systems, and 5) data management of CGM and AID systems in hospital.

“This is the most comprehensive and up-to-date guideline on the use of diabetes technology in the hospital now,” lead author Rodolfo J. Galindo, MD, told Medscape Medical News in an interview.

“Overall, most experts believe that CGM and AID have the potential to overcome the current limitations of glycemic monitoring in the hospital to improve patient outcomes, but we need research – first to get the approval and second to get widespread use,” said Galindo, medical chair of the hospital diabetes taskforce at Emory Healthcare System, Atlanta.
 

“COVID-19 changed everything”

The guideline is an update of a 2017 statement on hospital use of CGM. The new guideline adds AID systems (sometimes referred to as an artificial pancreas), which combines a CGM and insulin pump and uses an algorithm to guide insulin delivery, and is the first to be developed during the COVID-19 era.

The update had been planned prior to the pandemic, but the actual panel meeting took place in April 2020, after the US Food and Drug Administration allowed inpatient use of CGM despite lack of official approval.

“COVID-19 changed everything. ... We had to be more specific about how to implement CGM in these patients. The standard of care is hourly point-of-care glucose monitoring in the [ICU], and at least every 4 hours outside the ICU. With limited [personal protective equipment] and the burden on nursing it was unachievable,” Galindo explained.

In June 2020, Galindo and other guideline authors developed a COVID-19–specific document (also open-access), which goes more into detail about CGM and how to implement in-hospital use during the pandemic.

The current consensus guideline “provides a high-level review of the evidence by experts,” Galindo added.
 

Recommendations cover different technologies and hospital settings

The panel “strongly” advises that hospital providers consult with an inpatient diabetes team, if available, to help manage patients already using CGM prior to admission. Among other recommendations, they list several situations in which CGM data should not be relied upon for management decisions, including severe hyper- or hypoglycemia, diabetic ketoacidosis, or in patients with skin infections near the sensor site.

The panel also call for more research into outcomes for CGM continuation in the hospital and optimal implementation of both CGM and point-of-care glucose testing. For hospitals, strong recommendations include developing standard CGM data reports and workflows, as well as policies for CGM use.

Galindo pointed out: “A lot of hospitals have policies on that, but there aren’t many studies. It’s just that patients like it and it’s very hard to take it away from patients when they’re doing well.”

The section on CGM inpatient initiation is where COVID-19 plays the greatest role, which includes just one strong clinical practice recommendation: “Healthcare providers should consider prescribing CGM to reduce the need for frequent nurse contact for point-of-care glucose testing and the use of personal protective equipment for patients on isolation with highly contagious infectious diseases (eg, COVID-19).”

Strong recommendations also include a call for outcomes research and for hospitals to develop CGM protocols and educational tools for staff.

“We can do a study for approval but if administration and hospital policies aren’t there we’re not going to be able to use them,” Galindo noted.

For patients who already use AID systems – either the Medtronic 670G or Tandem Control IQ in the United States – the panel advises assessment to ensure the AID system is the most appropriate inpatient treatment, and the development of an alternative plan for diabetes management, if necessary. They also strongly recommend research in this area, and for hospitals to develop protocols for use of AID systems in various clinical situations.
 

Most detailed guidance addresses logistics and data management

Most of the strong recommendations regarding logistics are aimed at nursing staff, including receiving training in use of CGM and AID systems, confirming patient capacity, inspection of devices, and understanding when to administer a point-of-care glucose test.

Again, the panel calls for more data and for hospitals to develop policies and protocols for ensuring safe CGM and AID systems use, and when to avoid use.

Finally, they make one strong clinical recommendation regarding data management: “Healthcare providers should develop a set of core data elements and definitions for CGM data for inclusion in common data models and the electronic health record.”

That’s followed by a long list of relevant recommendations for research in the area, and for hospitals to integrate CGM and AID system data into their EHR systems.

This last area has proven particularly challenging, Galindo said. “Right now we do four point-of-care glucoses a day, and that goes right into the EHR, but with CGM it’s much more than that. How do we get all those data into the EHR and interpret it? Many steps need to be taken into consideration.”

Studies are being conducted in order to fulfill requirements for FDA approval of inpatient CGM use, he said, with data on implementation and inpatient AID system use to follow.

“More data will be available, triggered by the COVID-19 pandemic. However, the use of technology in the hospital goes beyond COVID-19,” he said

Galindo has reported receiving unrestricted research support to Emory for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly, and Valeritas. He is partially supported by research grants from the NIH/NIDDK.
 

This article first appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

Major thromboembolic complications and adverse cardiovascular events occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high use of thromboprophylaxis, in a new large observational U.S. study.

“Despite very high rate of antithrombotic prophylaxis there were a high rate of thromboembolic events suggesting that we are probably not providing enough thromboprophylaxis,” lead author Gregory Piazza, MD, Brigham and Women’s Hospital, Boston, said in an interview. 

“Standard prophylaxis as recommended in the guidelines is a low dose of low-molecular-weight heparin once daily, but these results suggest [patients] probably need higher doses,” he added.

However, Dr. Piazza cautioned that this is an observational study and randomized trials are needed to make changes in treatment strategies. Several such trials are currently underway.

The current study was published online ahead of print in the Nov. 3 issue of the Journal of the American College of Cardiology.
 

Rates similar to other very sick patients

The study showed that while thromboembolic complications were high, they were not as high as seen in some of the earlier studies from Asia and Europe, Dr. Piazza noted.

“The numbers we were seeing in early reports were so high we couldn’t figure out how that was possible,” he said. “Our study suggests that, in a U.S. population receiving thromboprophylaxis, the rate of thromboembolic complications [are] more in line with what we would expect to see in other very sick patients who end up in ICU.”

He suggested that the very high rates of thromboembolic complications in the early studies from Asia may have been because of the lack of thromboprophylaxis, which is not routine in hospitalized patients there. “Some of the earlier studies also used routine ultrasound and so picked up asymptomatic thrombotic events, which was not the case in our study. So our results are more representative of the U.S. population.”

Dr. Piazza attributed the high rate of thromboembolic complications being reported with COVID-19 to the sheer number of very sick patients being admitted to the hospital.

“We are accustomed to seeing a rare case of thrombosis despite prophylaxis in hospitalized patients, but we are seeing more in COVID patients. This is probably just because we have more critically ill patients,” he said.

“We are seeing an incredible influx of patients to the ICU that we have never experienced before, so the increase in thromboembolic complications is more obvious. In prior years we probably haven’t had enough critically ill patients at any one time to raise the flag about thromboprophylaxis,” he commented.

The study also found a high rate of cardiovascular complications. They are seeing an increase in the risk of MI, which is to be expected in such sick patients, but they also see quite a bit of new atrial fibrillation, myocarditis, and heart failure in patients who don’t always have underlying cardiovascular disease, he said.

“So this virus does appear to have a predilection to causing cardiovascular complications, but this is probably because it is making patients so sick,” Dr. Piazza said. “If flu was this virulent and resulted in such high rates of acute respiratory distress syndrome (ARDS), we would probably see similar cardiovascular complication rates.”

For the current report, the researchers analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through the Mass General Brigham integrated health network. Of these, 170 had been admitted to the ICU, 229 had been hospitalized but not treated in ICU, and 715 were outpatients. In terms of ethnicity, 22% were Hispanic/Latino and 44% were non-White. 

Cardiovascular risk factors were common, with 36% of patients having hypertension, 29% hyperlipidemia, and 18% diabetes. Prophylactic anticoagulation was prescribed in 89% of patients with COVID-19 in the intensive care cohort and 85% of those in the hospitalized non–intensive care setting.

Results showed that major arterial or venous thromboembolism (VTE) occurred in 35% of the intensive care cohort, 2.6% of those hospitalized but not treated in ICU, and 0% of outpatients.

Major adverse cardiovascular events occurred in 46% of the intensive care cohort, 6.1% of those hospitalized but non-ICU, and 0% of outpatients.

Symptomatic VTE occurred in 27% of those admitted to ICU, 2.2% of those hospitalized but non-ICU, and 0% of outpatients.

“We found that outpatients had a very low rate of thromboembolic complications, with the vast majority of the risk being in hospitalized patients, especially those in ICU,” Dr. Piazza said.

“These results suggest that we don’t need routine thromboprophylaxis for all outpatients with COVID-19, but there will probably be some patients who need it – those with risk factors for thromboembolism.”

Catheter- and device-associated deep vein thrombosis accounted for 76.9% of the DVTs observed in the study.

“Our finding of high frequency of catheter-associated DVT supports the judicious use of central venous catheters that have been widely implemented, especially in the ICU, to minimize recurrent health care team exposure and facilitate monitoring,” the researchers wrote.
 

ARDS biggest risk factor

Of all the markers of disease severity, the presence of ARDS had the strongest association with adverse outcomes, including major arterial or VTE, major adverse cardiovascular events, symptomatic VTE, and death.

“The severe inflammatory state associated with ARDS and other complications of COVID-19 and its resultant hypercoagulability may explain, at least in part, the high frequency of thromboembolic events. Improved risk stratification, utilizing biochemical markers of inflammation and activated coagulation as well as clinical indicators, such as ARDS, may play an important role in the early identification of patients with an increased likelihood of developing symptomatic VTE or arterial thrombosis,” the researchers wrote. “They may benefit from full- or intermediate-intensity antithrombotic therapy rather than prophylactic anticoagulation.”

They point out that this study provides a cross-sectional view of the cardiovascular complications of COVID-19 in a large health care network, consisting of two academic medical centers serving the greater Boston area, several community hospitals, and numerous outpatient care sites.

“The study incorporates a wide scope of clinically meaningful cardiovascular endpoints and utilizes a rigorous process of event adjudication. Although data on patients with COVID-19 in the ICU have been the subject of most reports, our study provides insights into the broad spectrum of all hospitalized and outpatient populations,” the authors noted.

“The high frequency of arterial or venous thromboembolism in hospitalized patients despite routine thromboprophylaxis suggests the need for improved risk stratification and enhanced preventive efforts,” they concluded.

The study is continuing, and the researchers expect to have data on 10,000 patients by the end of winter.
 

Wait for randomized trials

In an accompanying editorial, Robert McBane, MD, Mayo Clinic, Rochester, Minn., said that these data provide important real-world arterial and venous thrombotic event rates across a large, integrated health care network and an experienced roster of clinician-scientists devoted to thrombosis research.

Noting that whether to interpret these results as alarming or reassuring requires a comparison of expected thromboembolic event rates separate from the pandemic, he pointed out that, while the overall VTE rate among ICU patients was high, the vast majority of these events were attributable to central venous lines, and apart from these, the event rates do not appear inflated relative to prior published incidence rates from the pre–COVID-19 era.

“It is therefore important to resist the urge to overprevent or overtreat patients and expose them to the serious risks of major bleeding,” Dr. McBane wrote, adding that “the systematized approach to delivery of guideline-driven VTE prophylaxis across this large, integrated health network likely contributed to the relatively low rates of serious thrombotic outcomes reported.”

He further noted that, as the majority of VTE events were related to central venous lines in ICU patients, “this underscores the importance of a bundled care approach to central venous line management with daily assessment of the continued necessity of central access.

“A number of important clinical trials aimed at optimizing thromboprophylaxis during hospitalization, following hospital dismissal, and in ambulatory settings are underway. Until available, the lessons of thoughtful anticoagulant prophylaxis and treatment guidelines harvested from years of clinical research appear to apply,” he concluded.

This study was funded, in part, by a research grant from Janssen Pharmaceuticals. Dr. Piazza has received research grant support from EKOS Corporation, Bayer, Bristol-Myers Squibb/Pfizer, Portola Pharmaceuticals, and Janssen Pharmaceuticals; and has received consulting fees from Amgen, Pfizer, Boston Scientific, Agile, and Thrombolex. Dr. McBane reported no relevant disclosures.

A version of this article originally appeared on Medscape.com.

In 2016, there were an estimated 15,338,988 people living with cancer in the United States.¹ As such, it is important that hospitalists be proficient in managing oncologic emergencies that can arise during the natural history of cancer or from its treatment. This article will review three emergencies that are routinely encountered in the inpatient setting: malignant spinal cord compression (MSCC), hypercalcemia of malignancy (HCM), and febrile neutropenia (FN).

Case

vitanovski/Thinkstock.com

Mr. Williams is a 56-year-old man with newly diagnosed metastatic prostate cancer, diabetes mellitus, peptic ulcer disease, and hypertension. He is admitted with back pain and lower extremity weakness worsening over 2 weeks. He denies loss of sensation or bowel and bladder incontinence and can walk. MRI confirms cord compression at T10. What initial and subsequent steroid doses would be of most benefit to administer?

Malignant spinal cord compression

Treatment of MSCC usually aims to preserve function rather than reverse established deficits. MSCC from epidural tumor metastasis develops in 5%-14% of all cancer cases,² with back pain as the most common symptom. Nearly 60%-85% of patients have weakness at the time of diagnosis,³ and unfortunately, nearly two-thirds of patients will be nonambulatory at presentation.

While timely steroid administration in addition to definitive treatment may maintain ambulatory capacity at 1 year after therapy,⁴ there is no consensus on the optimal loading and maintenance dose and duration of steroids.
 

Overview of the data

Although there are no formal guidelines on optimal steroid dosing for MSCC, it is common practice for dexamethasone to be initially dosed at 10 mg followed by 4 mg every 4-6 hours.⁵ The use of higher doses of dexamethasone may result in improvement in neurologic deficits, but has higher risks for toxicity and is not universally supported in the literature.

A study conducted by Vecht and colleagues demonstrated few differences between initial high-dose and low-dose dexamethasone.⁶ Intravenous administration of either 10 mg or 100 mg dexamethasone, both followed by total 16 mg of dexamethasone orally per day, showed no significant difference in mobility or survival between the groups.

In a prospective study by Heimdal and colleagues that evaluated the relationship between dexamethasone dose and toxicity, higher doses of steroids had no meaningful impact on neurological symptoms and resulted in more severe side effects.⁷ Patients were either given 96-mg IV loading dose, gradually tapered over 2 weeks, or enrolled in the low-dose group in which they received 4-mg IV dexamethasone four times per day with a taper over 2 weeks. The high-dose group experienced side effects in 28.6% of patients, with 14.3% experiencing serious side effects. Meanwhile, 7.9% of the low-dose group exhibited some side effects, with none experiencing serious adverse effects.The high-dose group did not experience a significant increase in mobility (57.1 vs. 57.9%).
 

Key takeaways

Dexamthasone 10-mg oral or IV followed by 4 mg every 4-6 hours until definitive treatment is started is associated with improved neurologic outcomes and minimal adverse side effects. Higher doses of steroids are unlikely to offer more benefit. In patients with paraplegia or autonomic dysfunction, the ability to restore neurologic function is reduced and the burdens of steroid treatment may outweigh its benefits.⁵

Case continued

Mr. Williams completed treatment for MSCC but was still complaining of extreme lethargy and noticed an increase in thirst and no bowel movement in 5 days. His serum calcium was 14 mg/dL.

Hypercalcemia of malignancy

HCM is the most common paraneoplastic syndrome, observed in nearly 30% of patients with advanced cancer. It is a poor prognostic indicator, and approximately half of all patients with HCM will die within 30 days.⁸ Cancer is the most common reason for hypercalcemia in the inpatient setting⁹ and is most often associated with multiple myeloma, non–small cell lung cancer, breast cancer, renal cell carcinoma, non-Hodgkins lymphoma, and leukemia.

Hypercalcemia most often presents with cognitive changes and lethargy, anorexia, nausea, constipation, polyuria and polydipsia, and renal failure. Bradycardia and shortened QT interval are seen more with severe hypercalcemia.
 

Management of hypercalcemia of malignancy

Management of HCM depends on corrected calcium or ionized calcium levels, chronicity, degree of symptoms, and presence of renal failure. In general, mild asymptomatic hypercalcemia can be managed with outpatient care. Serum calcium greater than 14 mg/dL should be treated regardless of symptoms (Table 1).

For mild to moderate HCM, management involves saline administration to achieve euvolemia and calcitonin, which has temporizing effects. Early administration of IV bisphosphonates for moderate to severe HCM is beneficial because onset of action is 24-48 hours. Furosemide for management of HCM has fallen out of favor unless the patient develops hypervolemia. Denosumab has been Food and Drug Administration–approved for HCM refractory to bisphosphonate therapy and can manage HCM in 64% of patients who did not respond adequately to bisphosphonate therapy.¹⁰ Because it can be used in advanced renal failure without dose adjustment, it is first-line therapy in this population, although the risk for hypocalcemia is increased in renal failure. For patients with serum calcium greater than 18 mg/dL, worsening renal failure, or inability to tolerate IV fluids, dialysis with a low-calcium bath should be considered (Table 2).
 

Zoledronic acid versus pamidronate

A single dose of zoledronic acid normalizes the serum calcium concentration in 88% of patients, compared with 70% of those who received pamidronate, in a pooled analysis of two phase 3 trials.¹¹ The median duration of normocalcemia was longer for those receiving zoledronic acid (32-43 days vs. 18 days). The efficacy of the 4-mg and 8-mg zoledronic acid doses were similar, but the 4-mg dose was recommended because of renal toxicity and increased mortality associated with the higher dose.Despite this data, many specialists maintain that pamidronate, which is less expensive, is of similar clinical efficacy to ZA.¹²

Key takeaways

Management of HCM should be determined by the severity of the calcium level. The mainstay of treatment includes hydration with normal saline, calcitonin ,and bisphosphonate therapy; zoledronic acid is preferred over pamidronate. For patients refractory to bisphosphonates or patients with renal insufficiency, denosumab should be used.

Case continued: Febrile neutropenia

Febrile neutropenia is defined as a single oral temperature of 100.9° F or a temperature of 100.4° F sustained over a 1-hour period in a patient with absolute neutrophil count (ANC) less than 1,000 cells/mL or ANC expected to decrease to less than 500 cells/mL within a 48-hour period.¹³ Up to 30% of patients with solid tumors develop febrile neutropenia after chemotherapy, and nearly 80% of patients with hematologic malignancy or after hematopoietic stem cell therapy (HSCT) experience it.

Even though an infectious etiology is identified in only 30%-40% of cases, all patients with febrile neutropenia should initially receive at least empiric gram-negative coverage. The mortality rate is nearly 70% in neutropenic patients who do not receive empiric antibiotics and is reduced to 4%-20% with antibiotics.¹⁴
 

Risk stratification for febrile neutropenia and early discharge

Talcott’s Rules, the Multinational Association for Supportive Care in Cancer (MASCC) score, and the Clinical Index of Stable Febrile Neutropenia (CISNE) are validated tools to determine low-risk febrile neutropenia patients (Tables 3 and 4). The Infectious Diseases Society of America guidelines validated the use of MASCC in 2002 but found that CISNE had better performance than other tools. Coyne and colleagues conducted a retrospective cohort study to assess these two risk stratification tools in the ED and found that the CISNE was 98.3% specific for identifying adverse outcomes, whereas the MASCC was 54.2% specific.¹⁵

A study by Talcott and colleagues used Talcott’s Rules to identify low-risk febrile neutropenia patients, who were randomized to early discharge with home intravenous antibiotics versus continued inpatient management. There were no significant differences in the primary outcomes, defined as any change in clinical status requiring medical evaluation.¹⁶ Another study suggested that discharge after 24 hours based on clinical stability with outpatient oral antibiotics were noninferior to standard inpatient and intravenous antibiotic therapy.¹⁷ A Cochrane review in 2013 of 22 randomized controlled trials determined that oral antibiotics were an acceptable treatment for low-risk patients.¹⁸
 

Key takeaways

Though the MASCC is highly sensitive in identifying low-risk febrile neutropenia patients, it should be used with clinical caution because up to 11% of patients characterized as low risk developed severe complications.¹⁹ If a low-risk patient with solid tumor malignancy has adequate home support, lives within an hour of the hospital, and has access to follow-up within 72 hours, oral antibiotics and early discharge can be considered.

Dr. Chokshi is assistant professor in the division of hospital medicine at Mount Sinai Hospital, New York. Dr. Smith is associate professor in the division of hematology/oncology at Mount Sinai Hospital.

QUIZ

Mrs. Smith is a 64-year-old woman with endometrial cancer with temperature of 100.4° F at home. She takes no antibiotics, has no other medical history, and was sent in from clinic and admitted for further management. She feels well, and preliminary infectious workup is negative. She has been afebrile for more than 24 hours, and her ANC is 600 cells/mL.

Her son’s soccer game is tomorrow, and she would like to be present. Her family is involved in her care. Under what conditions can she be discharged?

A. She should not be discharged until full course of empiric intravenous antibiotics is completed.

B. Consider discharge in another 24 hours if she remains afebrile.

C. Discharge if low risk by MASCC or CISNE, with oral doses of levofloxacin or moxifloxacin or oral ciprofloxacin and amoxicillin/clavulanic acid.



Answer: C. The patient has a solid tumor malignancy, is low risk by both MASCC and CISNE, and can most likely be discharged if she is clinically stable or improved. A 7-day course of antibiotics is recommended with close follow-up.
 

References

1. SEER. Cancer of Any Site - Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/all.html. Accessed 2019 Jul 17.

2. Kwok Y et al. Clinical Approach to Metastatic Epidural Spinal Cord Compression. Hematol Oncol Clin North Am. 2006;20(6):1297-305.

3. Helweg-Larsen S et al. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys. 2000;46(5):1163-9.

4. Sørensen P et al. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: A randomised trial. Eur J Cancer. 1994;30(1):22-7.

5. Skeoch G et al. Corticosteroid treatment for metastatic spinal cord compression: A review. Global Spine J. 2017;7(3):272-9.

6. Vecht C et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39(9):1255-7.

7. Heimdal K et al. High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression. J Neurooncol. 1992;12(2):141-4.

8. Ralston S et al. Cancer-associated hypercalcemia: Morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990;112(7):499-504.

9. Lindner G et al. Hypercalcemia in the ED: Prevalence, etiology, and outcome. Am J Emerg Med. 2013;31(4):657-60.

10. Hu M et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst. 2013;105(18):1417-20.

11. Major P et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-67.

12. Stewart A. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-9.

13. Freifeld A et al. Executive summary: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):427-31.

14. Baden L et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(7):882-913.

15. Coyne C et al. Application of the MASCC and CISNE risk-stratification scores to identify low-risk febrile neutropenic patients in the emergency department. Ann Emerg Med. 2017;69(6):755-64.

16. Talcott J et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29(30):3977-83.

17. Innes H et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: A prospective randomised controlled single centre study. Br J Cancer. 2003;89(1):43-9.

18. Vidal L, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst. Rev. 2013.

19. Taplitz RA et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018;36(14):1443-53.

In 2016, there were an estimated 15,338,988 people living with cancer in the United States.¹ As such, it is important that hospitalists be proficient in managing oncologic emergencies that can arise during the natural history of cancer or from its treatment. This article will review three emergencies that are routinely encountered in the inpatient setting: malignant spinal cord compression (MSCC), hypercalcemia of malignancy (HCM), and febrile neutropenia (FN).

Case

vitanovski/Thinkstock.com

Mr. Williams is a 56-year-old man with newly diagnosed metastatic prostate cancer, diabetes mellitus, peptic ulcer disease, and hypertension. He is admitted with back pain and lower extremity weakness worsening over 2 weeks. He denies loss of sensation or bowel and bladder incontinence and can walk. MRI confirms cord compression at T10. What initial and subsequent steroid doses would be of most benefit to administer?

Malignant spinal cord compression

Treatment of MSCC usually aims to preserve function rather than reverse established deficits. MSCC from epidural tumor metastasis develops in 5%-14% of all cancer cases,² with back pain as the most common symptom. Nearly 60%-85% of patients have weakness at the time of diagnosis,³ and unfortunately, nearly two-thirds of patients will be nonambulatory at presentation.

While timely steroid administration in addition to definitive treatment may maintain ambulatory capacity at 1 year after therapy,⁴ there is no consensus on the optimal loading and maintenance dose and duration of steroids.
 

Overview of the data

Although there are no formal guidelines on optimal steroid dosing for MSCC, it is common practice for dexamethasone to be initially dosed at 10 mg followed by 4 mg every 4-6 hours.⁵ The use of higher doses of dexamethasone may result in improvement in neurologic deficits, but has higher risks for toxicity and is not universally supported in the literature.

A study conducted by Vecht and colleagues demonstrated few differences between initial high-dose and low-dose dexamethasone.⁶ Intravenous administration of either 10 mg or 100 mg dexamethasone, both followed by total 16 mg of dexamethasone orally per day, showed no significant difference in mobility or survival between the groups.

In a prospective study by Heimdal and colleagues that evaluated the relationship between dexamethasone dose and toxicity, higher doses of steroids had no meaningful impact on neurological symptoms and resulted in more severe side effects.⁷ Patients were either given 96-mg IV loading dose, gradually tapered over 2 weeks, or enrolled in the low-dose group in which they received 4-mg IV dexamethasone four times per day with a taper over 2 weeks. The high-dose group experienced side effects in 28.6% of patients, with 14.3% experiencing serious side effects. Meanwhile, 7.9% of the low-dose group exhibited some side effects, with none experiencing serious adverse effects.The high-dose group did not experience a significant increase in mobility (57.1 vs. 57.9%).
 

Key takeaways

Dexamthasone 10-mg oral or IV followed by 4 mg every 4-6 hours until definitive treatment is started is associated with improved neurologic outcomes and minimal adverse side effects. Higher doses of steroids are unlikely to offer more benefit. In patients with paraplegia or autonomic dysfunction, the ability to restore neurologic function is reduced and the burdens of steroid treatment may outweigh its benefits.⁵

Case continued

Mr. Williams completed treatment for MSCC but was still complaining of extreme lethargy and noticed an increase in thirst and no bowel movement in 5 days. His serum calcium was 14 mg/dL.

Hypercalcemia of malignancy

HCM is the most common paraneoplastic syndrome, observed in nearly 30% of patients with advanced cancer. It is a poor prognostic indicator, and approximately half of all patients with HCM will die within 30 days.⁸ Cancer is the most common reason for hypercalcemia in the inpatient setting⁹ and is most often associated with multiple myeloma, non–small cell lung cancer, breast cancer, renal cell carcinoma, non-Hodgkins lymphoma, and leukemia.

Hypercalcemia most often presents with cognitive changes and lethargy, anorexia, nausea, constipation, polyuria and polydipsia, and renal failure. Bradycardia and shortened QT interval are seen more with severe hypercalcemia.
 

Management of hypercalcemia of malignancy

Management of HCM depends on corrected calcium or ionized calcium levels, chronicity, degree of symptoms, and presence of renal failure. In general, mild asymptomatic hypercalcemia can be managed with outpatient care. Serum calcium greater than 14 mg/dL should be treated regardless of symptoms (Table 1).

For mild to moderate HCM, management involves saline administration to achieve euvolemia and calcitonin, which has temporizing effects. Early administration of IV bisphosphonates for moderate to severe HCM is beneficial because onset of action is 24-48 hours. Furosemide for management of HCM has fallen out of favor unless the patient develops hypervolemia. Denosumab has been Food and Drug Administration–approved for HCM refractory to bisphosphonate therapy and can manage HCM in 64% of patients who did not respond adequately to bisphosphonate therapy.¹⁰ Because it can be used in advanced renal failure without dose adjustment, it is first-line therapy in this population, although the risk for hypocalcemia is increased in renal failure. For patients with serum calcium greater than 18 mg/dL, worsening renal failure, or inability to tolerate IV fluids, dialysis with a low-calcium bath should be considered (Table 2).
 

Zoledronic acid versus pamidronate

A single dose of zoledronic acid normalizes the serum calcium concentration in 88% of patients, compared with 70% of those who received pamidronate, in a pooled analysis of two phase 3 trials.¹¹ The median duration of normocalcemia was longer for those receiving zoledronic acid (32-43 days vs. 18 days). The efficacy of the 4-mg and 8-mg zoledronic acid doses were similar, but the 4-mg dose was recommended because of renal toxicity and increased mortality associated with the higher dose.Despite this data, many specialists maintain that pamidronate, which is less expensive, is of similar clinical efficacy to ZA.¹²

Key takeaways

Management of HCM should be determined by the severity of the calcium level. The mainstay of treatment includes hydration with normal saline, calcitonin ,and bisphosphonate therapy; zoledronic acid is preferred over pamidronate. For patients refractory to bisphosphonates or patients with renal insufficiency, denosumab should be used.

Case continued: Febrile neutropenia

Febrile neutropenia is defined as a single oral temperature of 100.9° F or a temperature of 100.4° F sustained over a 1-hour period in a patient with absolute neutrophil count (ANC) less than 1,000 cells/mL or ANC expected to decrease to less than 500 cells/mL within a 48-hour period.¹³ Up to 30% of patients with solid tumors develop febrile neutropenia after chemotherapy, and nearly 80% of patients with hematologic malignancy or after hematopoietic stem cell therapy (HSCT) experience it.

Even though an infectious etiology is identified in only 30%-40% of cases, all patients with febrile neutropenia should initially receive at least empiric gram-negative coverage. The mortality rate is nearly 70% in neutropenic patients who do not receive empiric antibiotics and is reduced to 4%-20% with antibiotics.¹⁴
 

Risk stratification for febrile neutropenia and early discharge

Talcott’s Rules, the Multinational Association for Supportive Care in Cancer (MASCC) score, and the Clinical Index of Stable Febrile Neutropenia (CISNE) are validated tools to determine low-risk febrile neutropenia patients (Tables 3 and 4). The Infectious Diseases Society of America guidelines validated the use of MASCC in 2002 but found that CISNE had better performance than other tools. Coyne and colleagues conducted a retrospective cohort study to assess these two risk stratification tools in the ED and found that the CISNE was 98.3% specific for identifying adverse outcomes, whereas the MASCC was 54.2% specific.¹⁵

A study by Talcott and colleagues used Talcott’s Rules to identify low-risk febrile neutropenia patients, who were randomized to early discharge with home intravenous antibiotics versus continued inpatient management. There were no significant differences in the primary outcomes, defined as any change in clinical status requiring medical evaluation.¹⁶ Another study suggested that discharge after 24 hours based on clinical stability with outpatient oral antibiotics were noninferior to standard inpatient and intravenous antibiotic therapy.¹⁷ A Cochrane review in 2013 of 22 randomized controlled trials determined that oral antibiotics were an acceptable treatment for low-risk patients.¹⁸
 

Key takeaways

Though the MASCC is highly sensitive in identifying low-risk febrile neutropenia patients, it should be used with clinical caution because up to 11% of patients characterized as low risk developed severe complications.¹⁹ If a low-risk patient with solid tumor malignancy has adequate home support, lives within an hour of the hospital, and has access to follow-up within 72 hours, oral antibiotics and early discharge can be considered.

Dr. Chokshi is assistant professor in the division of hospital medicine at Mount Sinai Hospital, New York. Dr. Smith is associate professor in the division of hematology/oncology at Mount Sinai Hospital.

QUIZ

Mrs. Smith is a 64-year-old woman with endometrial cancer with temperature of 100.4° F at home. She takes no antibiotics, has no other medical history, and was sent in from clinic and admitted for further management. She feels well, and preliminary infectious workup is negative. She has been afebrile for more than 24 hours, and her ANC is 600 cells/mL.

Her son’s soccer game is tomorrow, and she would like to be present. Her family is involved in her care. Under what conditions can she be discharged?

A. She should not be discharged until full course of empiric intravenous antibiotics is completed.

B. Consider discharge in another 24 hours if she remains afebrile.

C. Discharge if low risk by MASCC or CISNE, with oral doses of levofloxacin or moxifloxacin or oral ciprofloxacin and amoxicillin/clavulanic acid.



Answer: C. The patient has a solid tumor malignancy, is low risk by both MASCC and CISNE, and can most likely be discharged if she is clinically stable or improved. A 7-day course of antibiotics is recommended with close follow-up.
 

References

1. SEER. Cancer of Any Site - Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/all.html. Accessed 2019 Jul 17.

2. Kwok Y et al. Clinical Approach to Metastatic Epidural Spinal Cord Compression. Hematol Oncol Clin North Am. 2006;20(6):1297-305.

3. Helweg-Larsen S et al. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys. 2000;46(5):1163-9.

4. Sørensen P et al. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: A randomised trial. Eur J Cancer. 1994;30(1):22-7.

5. Skeoch G et al. Corticosteroid treatment for metastatic spinal cord compression: A review. Global Spine J. 2017;7(3):272-9.

6. Vecht C et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39(9):1255-7.

7. Heimdal K et al. High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression. J Neurooncol. 1992;12(2):141-4.

8. Ralston S et al. Cancer-associated hypercalcemia: Morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990;112(7):499-504.

9. Lindner G et al. Hypercalcemia in the ED: Prevalence, etiology, and outcome. Am J Emerg Med. 2013;31(4):657-60.

10. Hu M et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst. 2013;105(18):1417-20.

11. Major P et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-67.

12. Stewart A. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-9.

13. Freifeld A et al. Executive summary: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):427-31.

14. Baden L et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(7):882-913.

15. Coyne C et al. Application of the MASCC and CISNE risk-stratification scores to identify low-risk febrile neutropenic patients in the emergency department. Ann Emerg Med. 2017;69(6):755-64.

16. Talcott J et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29(30):3977-83.

17. Innes H et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: A prospective randomised controlled single centre study. Br J Cancer. 2003;89(1):43-9.

18. Vidal L, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst. Rev. 2013.

19. Taplitz RA et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018;36(14):1443-53.

In 2016, there were an estimated 15,338,988 people living with cancer in the United States.¹ As such, it is important that hospitalists be proficient in managing oncologic emergencies that can arise during the natural history of cancer or from its treatment. This article will review three emergencies that are routinely encountered in the inpatient setting: malignant spinal cord compression (MSCC), hypercalcemia of malignancy (HCM), and febrile neutropenia (FN).

Case

vitanovski/Thinkstock.com

Mr. Williams is a 56-year-old man with newly diagnosed metastatic prostate cancer, diabetes mellitus, peptic ulcer disease, and hypertension. He is admitted with back pain and lower extremity weakness worsening over 2 weeks. He denies loss of sensation or bowel and bladder incontinence and can walk. MRI confirms cord compression at T10. What initial and subsequent steroid doses would be of most benefit to administer?

Malignant spinal cord compression

Treatment of MSCC usually aims to preserve function rather than reverse established deficits. MSCC from epidural tumor metastasis develops in 5%-14% of all cancer cases,² with back pain as the most common symptom. Nearly 60%-85% of patients have weakness at the time of diagnosis,³ and unfortunately, nearly two-thirds of patients will be nonambulatory at presentation.

While timely steroid administration in addition to definitive treatment may maintain ambulatory capacity at 1 year after therapy,⁴ there is no consensus on the optimal loading and maintenance dose and duration of steroids.
 

Overview of the data

Although there are no formal guidelines on optimal steroid dosing for MSCC, it is common practice for dexamethasone to be initially dosed at 10 mg followed by 4 mg every 4-6 hours.⁵ The use of higher doses of dexamethasone may result in improvement in neurologic deficits, but has higher risks for toxicity and is not universally supported in the literature.

A study conducted by Vecht and colleagues demonstrated few differences between initial high-dose and low-dose dexamethasone.⁶ Intravenous administration of either 10 mg or 100 mg dexamethasone, both followed by total 16 mg of dexamethasone orally per day, showed no significant difference in mobility or survival between the groups.

In a prospective study by Heimdal and colleagues that evaluated the relationship between dexamethasone dose and toxicity, higher doses of steroids had no meaningful impact on neurological symptoms and resulted in more severe side effects.⁷ Patients were either given 96-mg IV loading dose, gradually tapered over 2 weeks, or enrolled in the low-dose group in which they received 4-mg IV dexamethasone four times per day with a taper over 2 weeks. The high-dose group experienced side effects in 28.6% of patients, with 14.3% experiencing serious side effects. Meanwhile, 7.9% of the low-dose group exhibited some side effects, with none experiencing serious adverse effects.The high-dose group did not experience a significant increase in mobility (57.1 vs. 57.9%).
 

Key takeaways

Dexamthasone 10-mg oral or IV followed by 4 mg every 4-6 hours until definitive treatment is started is associated with improved neurologic outcomes and minimal adverse side effects. Higher doses of steroids are unlikely to offer more benefit. In patients with paraplegia or autonomic dysfunction, the ability to restore neurologic function is reduced and the burdens of steroid treatment may outweigh its benefits.⁵

Case continued

Mr. Williams completed treatment for MSCC but was still complaining of extreme lethargy and noticed an increase in thirst and no bowel movement in 5 days. His serum calcium was 14 mg/dL.

Hypercalcemia of malignancy

HCM is the most common paraneoplastic syndrome, observed in nearly 30% of patients with advanced cancer. It is a poor prognostic indicator, and approximately half of all patients with HCM will die within 30 days.⁸ Cancer is the most common reason for hypercalcemia in the inpatient setting⁹ and is most often associated with multiple myeloma, non–small cell lung cancer, breast cancer, renal cell carcinoma, non-Hodgkins lymphoma, and leukemia.

Hypercalcemia most often presents with cognitive changes and lethargy, anorexia, nausea, constipation, polyuria and polydipsia, and renal failure. Bradycardia and shortened QT interval are seen more with severe hypercalcemia.
 

Management of hypercalcemia of malignancy

Management of HCM depends on corrected calcium or ionized calcium levels, chronicity, degree of symptoms, and presence of renal failure. In general, mild asymptomatic hypercalcemia can be managed with outpatient care. Serum calcium greater than 14 mg/dL should be treated regardless of symptoms (Table 1).

For mild to moderate HCM, management involves saline administration to achieve euvolemia and calcitonin, which has temporizing effects. Early administration of IV bisphosphonates for moderate to severe HCM is beneficial because onset of action is 24-48 hours. Furosemide for management of HCM has fallen out of favor unless the patient develops hypervolemia. Denosumab has been Food and Drug Administration–approved for HCM refractory to bisphosphonate therapy and can manage HCM in 64% of patients who did not respond adequately to bisphosphonate therapy.¹⁰ Because it can be used in advanced renal failure without dose adjustment, it is first-line therapy in this population, although the risk for hypocalcemia is increased in renal failure. For patients with serum calcium greater than 18 mg/dL, worsening renal failure, or inability to tolerate IV fluids, dialysis with a low-calcium bath should be considered (Table 2).
 

Zoledronic acid versus pamidronate

A single dose of zoledronic acid normalizes the serum calcium concentration in 88% of patients, compared with 70% of those who received pamidronate, in a pooled analysis of two phase 3 trials.¹¹ The median duration of normocalcemia was longer for those receiving zoledronic acid (32-43 days vs. 18 days). The efficacy of the 4-mg and 8-mg zoledronic acid doses were similar, but the 4-mg dose was recommended because of renal toxicity and increased mortality associated with the higher dose.Despite this data, many specialists maintain that pamidronate, which is less expensive, is of similar clinical efficacy to ZA.¹²

Key takeaways

Management of HCM should be determined by the severity of the calcium level. The mainstay of treatment includes hydration with normal saline, calcitonin ,and bisphosphonate therapy; zoledronic acid is preferred over pamidronate. For patients refractory to bisphosphonates or patients with renal insufficiency, denosumab should be used.

Case continued: Febrile neutropenia

Febrile neutropenia is defined as a single oral temperature of 100.9° F or a temperature of 100.4° F sustained over a 1-hour period in a patient with absolute neutrophil count (ANC) less than 1,000 cells/mL or ANC expected to decrease to less than 500 cells/mL within a 48-hour period.¹³ Up to 30% of patients with solid tumors develop febrile neutropenia after chemotherapy, and nearly 80% of patients with hematologic malignancy or after hematopoietic stem cell therapy (HSCT) experience it.

Even though an infectious etiology is identified in only 30%-40% of cases, all patients with febrile neutropenia should initially receive at least empiric gram-negative coverage. The mortality rate is nearly 70% in neutropenic patients who do not receive empiric antibiotics and is reduced to 4%-20% with antibiotics.¹⁴
 

Risk stratification for febrile neutropenia and early discharge

Talcott’s Rules, the Multinational Association for Supportive Care in Cancer (MASCC) score, and the Clinical Index of Stable Febrile Neutropenia (CISNE) are validated tools to determine low-risk febrile neutropenia patients (Tables 3 and 4). The Infectious Diseases Society of America guidelines validated the use of MASCC in 2002 but found that CISNE had better performance than other tools. Coyne and colleagues conducted a retrospective cohort study to assess these two risk stratification tools in the ED and found that the CISNE was 98.3% specific for identifying adverse outcomes, whereas the MASCC was 54.2% specific.¹⁵

A study by Talcott and colleagues used Talcott’s Rules to identify low-risk febrile neutropenia patients, who were randomized to early discharge with home intravenous antibiotics versus continued inpatient management. There were no significant differences in the primary outcomes, defined as any change in clinical status requiring medical evaluation.¹⁶ Another study suggested that discharge after 24 hours based on clinical stability with outpatient oral antibiotics were noninferior to standard inpatient and intravenous antibiotic therapy.¹⁷ A Cochrane review in 2013 of 22 randomized controlled trials determined that oral antibiotics were an acceptable treatment for low-risk patients.¹⁸
 

Key takeaways

Though the MASCC is highly sensitive in identifying low-risk febrile neutropenia patients, it should be used with clinical caution because up to 11% of patients characterized as low risk developed severe complications.¹⁹ If a low-risk patient with solid tumor malignancy has adequate home support, lives within an hour of the hospital, and has access to follow-up within 72 hours, oral antibiotics and early discharge can be considered.

Dr. Chokshi is assistant professor in the division of hospital medicine at Mount Sinai Hospital, New York. Dr. Smith is associate professor in the division of hematology/oncology at Mount Sinai Hospital.

QUIZ

Mrs. Smith is a 64-year-old woman with endometrial cancer with temperature of 100.4° F at home. She takes no antibiotics, has no other medical history, and was sent in from clinic and admitted for further management. She feels well, and preliminary infectious workup is negative. She has been afebrile for more than 24 hours, and her ANC is 600 cells/mL.

Her son’s soccer game is tomorrow, and she would like to be present. Her family is involved in her care. Under what conditions can she be discharged?

A. She should not be discharged until full course of empiric intravenous antibiotics is completed.

B. Consider discharge in another 24 hours if she remains afebrile.

C. Discharge if low risk by MASCC or CISNE, with oral doses of levofloxacin or moxifloxacin or oral ciprofloxacin and amoxicillin/clavulanic acid.



Answer: C. The patient has a solid tumor malignancy, is low risk by both MASCC and CISNE, and can most likely be discharged if she is clinically stable or improved. A 7-day course of antibiotics is recommended with close follow-up.
 

References

1. SEER. Cancer of Any Site - Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/all.html. Accessed 2019 Jul 17.

2. Kwok Y et al. Clinical Approach to Metastatic Epidural Spinal Cord Compression. Hematol Oncol Clin North Am. 2006;20(6):1297-305.

3. Helweg-Larsen S et al. Prognostic factors in metastatic spinal cord compression: a prospective study using multivariate analysis of variables influencing survival and gait function in 153 patients. Int J Radiat Oncol Biol Phys. 2000;46(5):1163-9.

4. Sørensen P et al. Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: A randomised trial. Eur J Cancer. 1994;30(1):22-7.

5. Skeoch G et al. Corticosteroid treatment for metastatic spinal cord compression: A review. Global Spine J. 2017;7(3):272-9.

6. Vecht C et al. Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology. 1989;39(9):1255-7.

7. Heimdal K et al. High incidence of serious side effects of high-dose dexamethasone treatment in patients with epidural spinal cord compression. J Neurooncol. 1992;12(2):141-4.

8. Ralston S et al. Cancer-associated hypercalcemia: Morbidity and mortality. Clinical experience in 126 treated patients. Ann Intern Med. 1990;112(7):499-504.

9. Lindner G et al. Hypercalcemia in the ED: Prevalence, etiology, and outcome. Am J Emerg Med. 2013;31(4):657-60.

10. Hu M et al. Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. J Natl Cancer Inst. 2013;105(18):1417-20.

11. Major P et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-67.

12. Stewart A. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-9.

13. Freifeld A et al. Executive summary: Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52(4):427-31.

14. Baden L et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(7):882-913.

15. Coyne C et al. Application of the MASCC and CISNE risk-stratification scores to identify low-risk febrile neutropenic patients in the emergency department. Ann Emerg Med. 2017;69(6):755-64.

16. Talcott J et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29(30):3977-83.

17. Innes H et al. Oral antibiotics with early hospital discharge compared with in-patient intravenous antibiotics for low-risk febrile neutropenia in patients with cancer: A prospective randomised controlled single centre study. Br J Cancer. 2003;89(1):43-9.

18. Vidal L, et al. Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst. Rev. 2013.

19. Taplitz RA et al. Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America clinical practice guideline update. J Clin Oncol. 2018;36(14):1443-53.